Protective autophagy
Why pancreatic cancer is not afraid of immunotherapy
Kirill Stasevich, Science and Life (nkj.ru )
Immunity should destroy not only viruses with bacteria, but also malignant cells. But malignant cells have various tricks that allow them to remain invisible to the immune system. However, if the immune system, so to speak, opens its eyes, it will see the tumor and begin to destroy it. The essence of immunotherapy is to activate the anti-cancer properties of immunity. Different approaches are used here, and two immunotherapeutic discoveries were even recently awarded the Nobel Prize.
But different types of cancer react differently to immunotherapy, and pancreatic cancer in this sense is one of the most persistent. He does not react just to the "Nobel" methods of therapy based on the fact that the brakes are literally turned off in the immune system.
The immune system has fuses, cells and molecules that make sure that the protective reaction is on the case and adequate to the threat – so that the immune system does not fall into aggression without a reason and that the immune activity subsides as the danger disappears. These fuses include PD-1 and CTLA-4 proteins sitting on the surface of T-lymphocytes, which usually destroy diseased cells, including cancer cells.
PD-1 and CTLA-4 calm T-lymphocytes, that is, if PD-1 and CTLA-4 are active, T-lymphocytes do not kill anyone. Cancer cells just keep PD-1 and CTLA-4 on, so the immune system ignores the tumor. But if you turn off PD-1 and CTLA-4 – in other words, break the brakes on lymphocytes – then the immune system will begin to hunt cancer cells.
But even T-lymphocytes with broken brakes still somehow do not touch pancreatic cancer cells. There may be several reasons for this. Firstly, the activity of immune cells depends not only on these two proteins. And in the cancerous tumor itself, there may be some other cells that lull the vigilance of T-lymphocytes using some other cellular-molecular mechanisms. Secondly, cancer cells themselves may have features due to which lymphocytes simply cannot detect them.
Why do immune cells start attacking cancer cells? Because immune cells sense special molecules on the surface of cancer cells that give out cancer cells from the head. But special cancer molecules do not appear on the surface of cells just like that. Proteins of the major histocompatibility complex (MHC), including human leukocyte antigens (human leukocyte antigens, HLA) serve as something like a cellular passport: they sit on the cell membrane and hold fragments of various cellular proteins.
Immune cells check that they are holding MHC proteins: if they hold fragments of ordinary cellular proteins, then the cell is healthy and it is not necessary to touch it; if they hold fragments of viral or bacterial molecules, then the cell is infected and it needs to be destroyed. And if MHC proteins hold fragments of other proteins that are inherent in cancer cells, then such a cell also needs to be destroyed.
It is said that MHC proteins are engaged in the presentation of antigens – molecules to which the immune system can respond. And if a mutation occurs in the MHC genes, then they can no longer show different antigens to immune cells, or they show them poorly. Some cancer cells are saved from immunity precisely due to the fact that their MHC genes are mutated.
But pancreatic cancer is special in this sense: mutations in the MHC genes are found in no more than 1% of cases, and at the same time in pancreatic cancer cells in more than 60% of cases, the level of MHC is lower than it should be, or there are no MHC at all (which is especially noticeable in metastatic cells).
Researchers from New York University write in Nature that pancreatic cancer cells get rid of MHC proteins using an important cellular process called autophagy (Yamamoto et al., Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I). With the help of autophagy, the cell digests proteins and whole organelles that have become unnecessary in order to make something useful again from their spare parts (by the way, they also gave for deciphering the mechanism of autophagy The Nobel Prize a few years ago). What needs to be digested, split, and disassembled is marked with a special label, after which the labeled garbage is packed into a membrane bubble – an autophagosome; then the autophagosome merges with another membrane bubble – a lysosome, which contains splitting enzymes.
And it turned out that pancreatic cancer cells have few MHC proteins on the surface – but a lot of MHC proteins in autophagosomes, "self-digesting vesicles". It was also possible to find a receptor protein that sends MHC proteins for cleavage. Autophagy can be suppressed either by genetic engineering or by certain substances (for example, chloroquine, which is now being vigorously discussed as one of the remedies against the SARS-CoV-2 coronavirus).
If autophagy was somehow suppressed in experimental mice with pancreatic cancer, then T-lymphocytes were activated in mice, whose task was to destroy cancer cells - these T–lymphocytes massively came to the tumor, and if the mice were also given immunotherapeutic drugs, then the disease in animals noticeably receded.
Pancreatic cancer cells (green) use a common waste disposal process called autophagy to hide the marks on their surfaces (top), but blocking this process leaves most of the marks in place (bottom), which can then be detected by attacking T cells (blue).
In fact, according to the Nature portal (Pancreatic cancer hidden in plain sight), experts have long known that autophagy is very, very important for pancreatic cancer; it was only unclear what exactly autophagy is so useful for cancer cells. Also, one of the stages of autophagy has been blocked for a relatively long time; both substances, which have been used for decades as a remedy for malaria, were tested against malignant tumors, but the results were not too outstanding then.
It is possible that after the new data, interest in the anticancer properties of chloroquine will resurrect again, and pancreatic cancer can be successfully treated with immunotherapeutic methods enhanced by this antimalarial agent or its analogue.
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